The overall objective of the Program is to characterize important host regulatory mechanisms and signaling pathways that govern the induction and regulation of innate and acquired mucosal immune and inflammatory responses in the intestinal tract to enteric microbes and their products. The Program is designed with 4 Research Units and 4 Cores. Three Research Units and all 4 Cores are currently funded through 6/30/2014. This supplementary application requests a change in the research goals and Project Leader of Research Unit 4, as initially submitted and funded, for the 3 year period 7/01/2011-6/30/2014. The proposed Project leader for replacement Research Unit 4 is Dr. Michael Karin, who has a proven record of being highly interactive with the 3 other Research Unit leaders. A revised Research Unit 4, under Dr. Karin's leadership, will greatly enhance the ability of the Program to achieve maximum productivity focused on its overall objectives. Dr. Karin's project "Role of I?B kinase subunits in mucosal immune homeostasis" has 4 aims that are closely aligned and integrated with the 3 ongoing Research Units. Research Unit 4, as proposed, is highly innovative and uses state-of-the-art approaches to address the important roles and mechanisms by which IKKa and IKK[unreadable] regulate intestinal mucosal homeostasis and inflammation. This Unit will interact extensively with Research Unit 1 that investigates the regulation of mucosal innate immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine using an attaching and effacing lesion inducing enteric pathogen and rotavirus to probe the host response, with Research Unit 2 that investigates intestinal mucosal responses that determine immune defenses against the minimally invasive enteric pathogen Giardia, which elicits strong protective immunity in the absence of mucosal inflammation, and with Research Unit 3 that investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core. PUBLIC HEALTH RELEVANCE: The Intestinal mucosa is a major site of interaction between the host and enteric pathogens that cause diarrheal illness, morbidity and death among millions worldwide each year. These studies will elucidate mechanisms and pathways that determine how the host responds to infection with enteric microbes. We anticipate this research will result in the identification of cellular and molecular targets that can be used and manipulated to achieve more effective host protective immunity to enteric infections through pharmacological, molecular, cellular and vaccine interventions.